rs1555260207
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000545.8(HNF1A):c.4del(p.Val2?) variant causes a frameshift, start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: not found (cov: 32)
Consequence
HNF1A
NM_000545.8 frameshift, start_lost
NM_000545.8 frameshift, start_lost
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.40
Genes affected
HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 441 pathogenic variants in the truncated region.
PS1
?
Another start lost variant in NM_000545.8 (HNF1A) was described as [Pathogenic] in ClinVar as 502525
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-120978770-TG-T is Pathogenic according to our data. Variant chr12-120978770-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 447493.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.4del | p.Val2? | frameshift_variant, start_lost | 1/10 | ENST00000257555.11 | |
HNF1A | NM_001306179.2 | c.4del | p.Val2? | frameshift_variant, start_lost | 1/10 | ||
HNF1A | NM_001406915.1 | c.4del | p.Val2? | frameshift_variant, start_lost | 1/9 | ||
HNF1A | XM_024449168.2 | c.4del | p.Val2? | frameshift_variant, start_lost | 1/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.4del | p.Val2? | frameshift_variant, start_lost | 1/10 | 1 | NM_000545.8 | P4 | |
HNF1A-AS1 | ENST00000619441.1 | n.128+1873del | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Maturity onset diabetes mellitus in young Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs1555260207 with MODY3. - |
Monogenic diabetes Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Feb 22, 2022 | The c. 4delG variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 2 (NM_000545.6), adding 4 novel amino acids before encountering a stop codon (p.(Val2PhefsTer4)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, the variant is absent from gnomAD v2.1.1 (PM2_Supporting). Lastly, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting, PP4. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 02, 2017 | - - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at